Process of forming minute capsules

ABSTRACT

A PROCESS FOR FORMING MINUTE CAPSULES IN A MANUFACTURING VEHICLE WHICH COMPRISES (A) ESTABLISHING AN AGITATED SYSTEM CONSISTING OF A LIQUID VEHICLE CONSTITUTING A MAJOR PORTION OF SAID SYSTEM BY VOLUME AND FORMING A CONTINUOUS LIQUID FIRST PHASE, A SECOND PHASE DISPERSED IN SAID LIQUID VEHICLE CONSISTING OF MINUTE, MOBILE ENTITIES OF CORE MATERIAL, AND A THIRD PHASE DISPERSED IN SAID LIQUID VEHICLE CONSISTING OF MINUTE, MOBILE, NON-AQUEOUS, LIQUID ENTITIES OF A WALL-FORMING SOLUTION OF A POLYMERIC MATERIAL HAVING A VISCOSITY SUCH THAT SAID SOLUTION OF WALL-FORMING POLYMERIC MATERIAL MAINTAINS ITSELF ABOUT THE CORE MATERIAL IN THE AGITATED SYSTEM, THE SAID CORE MATERIAL BEING WETTABLE BY SAID WALL-FORMING SOLUTION AND THE SAID THREE PHASES BEING MUTUALLY INCOMPATIBLE, WHEREBY SAID WALLFORMING SOLUTION DEPOSITS ON AND AROUND SAID CORE ENTITIES TO FORM A CONTINUOUS LIQUID PROTECTIVE WALL, AND (B) SUBSEQUENTLY HARDENING THE WALLS SO FORMED.

United States Patent ()1 :"fice 3,748,277 Patented July 24, 1973 U.S.Cl. 252-316 24 Claims ABSTRACT OF THE DISCLOSURE A process for formingminute capsules in a manufacturing vehicle which comprises (a)establishing an agitated system consisting of a liquid vehicleconstituting a major portion of said system 'by volume and forming acontinuous liquid first phase, a second phase dispersed in said liquidvehicle consisting of minute, mobile entities of core material, and athird phase dispersed in said liquid vehicle consisting of minute,mobile, non-aqueous, liquid entities of a wall-forming solution of apolymeric material having a viscosity such that said solution ofwall-forming polymeric material maintains itself about the core materialin the agitated system, the said core material being wettable by saidwall-forming solution and the said three phases being mutuallyincompatible, whereby said wallforming solution deposits on and aroundsaid core entities to form a continuous liquid protective wall, and (b)subsequently hardening the walls so formed.

This application is a continuation-in-part of U.S. patent applicationSer. No. 781,918, filed Dec. 22, 1958, by John G. Wagner, and nowabandoned.

This invention relates to a process for providing a protective coatingor capsule wall for a wide variety of materials and more particularly toa process for providing a protective coating for liquid and solidnucleus or core materials in a liquid manufacturing vehicle throughestablishment of a three phase system, one phase of which is acoacervate solution of a wall-forming polymer in an organic liquid, andto the coated core material provided thereby. Further, this inventionrelates to a process of manufacturing minute capsules en masse in anorganic liquid manufacturing vehicle and to the capsule product, eachcapsule comprising a core and a seamless Protecting wall surrounding thecore. By minute capsules are meant capsules from a few microns toseveral thousand microns and possibly somewhat larger in average size.

In the art of providing protective coatings for various materials andarticles, many processes have been utilized. Familiar examples includethe following: spray coating, dip coating, pan coating, roll-applicatorcoating, and brush coating. Essentially, these methods are suitable forcoating materials and articles of relatively large surface area perunit. The unit referred to is a single piece or article; for example, anindividual nut or bolt, an individual motor, an individual piece ofcandy, an individual medicinal tablet, an individual sheet of paper orpaper board, and the like.

Coacervation is a phenomenon that has been used in the past to effect anencapsulation, en masse, of minute core materials. However, prior to thepresent invention, processes for the microencapsulation, en masse, ofnucleus or core material have been restricted to systems wherein thewall-forming or wrapping about the core material was conducted in anaqueous medium. These prior techniques are described, for example, inUnited States Reissue Patent No. 24,899, issued to Barrett K. Green onNov. 29, 1960, and assigned to the assignee herein. Such processes donot yield a capsular product wherein the core material is substantiallywater-soluble.

It is an object, therefore, of the present invention to provide acoating or encapsulation process broadly applicable to the coating ofaqueous and water-soluble liquid and solid particles.

Other objects will be apparent to those skilled in the art to which thisinvention pertains.

The following are related United States patent applications directed tospecific process inventions referred to herein, without limitation, asexamples of processes employing the broader invention of thisapplication and its above-identified parent application.

(1) Ser. No. 13,725, filed Mar. 9, 1960, by Thomas C. Powell et 211.,now abandoned.

(II) Ser. No. 192,071, filed May 3, 1962, and now U.S. Pat. No.3,415,758, as a continuation-in-part of Ser. No. 13,725, now abandoned,by Thomas C. Powell et al.

In a specific form, the present invention comprises preparing a solutionof a liquid-phase-forming macromolecular polymer in a first non-aqueousliquid, forming a dispersion of liquid or solid particles in thissolution, adding to the thus-prepared dispersion a second non-aqueousliquid miscible with the first liquid and a non-solvent to themacromolecular polymer and to the liquid or solid particles to be coatedto cause a liquid-liquid phase separation into a macromolecularpolymer-rich, non-aqueous liquid phase (coacervate phase) and amacromolecular, relative- 1y polymer-poor, non-aqueous liquid phase. Themacromolecular polymer-rich phase coats the liquid or solid particles.The coating is then set to impart rigidity thereto. The coated particlesare separated from the liqruids, washed, separated from the wash medium,and dried. Optionally, the coating or capsule wall may be hardened toimpart stability thereto, which in some cases also reduces permeability.

In its broadest aspect, the subject invention comprises acapsule-forming process which involves the establishment of a systemthat is characterized as follows (these terms being defined below):

(1) It is in an agitated state;

(2) It comprises the following three phases, characterized first of allby being mutually incompatible (as defined hereinafter) and furtherchaarcterized, respectively, as being:

(a) a continuous liquid phase vehicle that constitutes a major portionby volume of the three phases in total,

(b) a discontinuous phase of minute, mobile entities of core material,either solid or liquid, dispersed in the vehicle and constituting aminor portion by volume of the three phases in total, and

(c) a discontinuous coacervate phase of minute, mobile entities ofwall-forming material dispersed in the vehicle and constituted by anon-aqueous solution of one or more polymeric substances, the solutionbeing capable of wetting the core material and having a viscositysufiicient to maintain itself about the core material against theshearing or other forces and yet of a viscosity that permits theformation of a seamless wall of polymeric material.

This agitated system results in a deposit of the wallforming materialaround the entities of core material. By reason of the viscosity andvolume relation of the dispersed phase of wall-forming polymer solution,that phase is capable of deposit around the dispersed entities of corematerial and is also capable, after deposit, of maintaining itself as awall against the shearing forces that exist as an incident of therequired agitation of the system. The deposits quickly accumulate to amaximum thickness, which may be varied by varying the amount of the wallmaterial provided and the degree and type of agitation used, and whichmay vary in accordance with the need for protection of the core materialand the protective characteristics of the wall-forming material selectedfor use.

Depending on the nature of the core material and that of the wallmaterial, the embryonic capsules, prior to hardening, formed in theliquid vehicle by this system are more or less durable. Varioussupplemental treatments of the capsules so formed may be employed toharden their walls and thereby impart to them greater durability andgreater impermeability relative to the core material and theenvironment, among other properties. Suitable procedures are set forthhereinafter.

A further measure of protection is to cause deposit of an additionalsurrounding wall of polymeric material by a succeeding encapsulationstep in which these initiallyformed capsules, with or without hardeningtreatment, serve as the core entities.

This new process of making capsules en masse in a liquid vehicle byestablishing a system as defined above differs from the previously knownsystem of United States Pats. Nos. 2,800,457 and 2,800,458 (Reissue24,899) in that the present system is non-aqueous, and differs inparticulars with respect to the classes of materials that canconstitute, and that preferably constitute, the vehicle, the capsulecores, and the capsule wall, respectively. This new process isapplicable to the encapsulation of a wide range of core materials,including many that cannot be encapsulated by the processes described inthose patents, and uniquely applicable to the encapsulation ofwater-soluble solids, and also through conjoint use of a furtherinvention of Thomas C. Powell et al. respecting the use of polymericmaterial having special polar groups (described in United States patentapplication Ser. No. 192,070, filed May 3, 1962 and now abandoned) iscapable of encapsulating water and waterlike liquid core materials.

Former specifically-disclosed processes employing a liquid manufacturingvehicle were incapable of usefully encapsulating water-soluble solidsand water or water-like liquids. Such known processes of making capsulesen masse employed an aqueous vehicle and a three-component system inwhich a deposit of hydrophilic wall-forming polymeric material arounddispersed core entities would occur. This involved an aqueous Vehicleand an aqueous solution of hydrophilic wall-forming polymeric material(that is, a coacervate phase having an aqueous liquid as the associatedliquid), which precluded the use of water-soluble solids or aqueous corematerials. Of course, slightly water-soluble core material could be usedwith prior systems if the vehicle and the aqueous wallforming solutionwere saturated with them and the presence of the water-soluble materialsdid not adversely affect the protective coating as it would in manyinstances.

It has been discovered that a non-aqueous coacervate phase may beutilized, such that, if the polymeric material of the capsule wall, thesolvent therefor, and the vehicle are selected to meet the foregoingcriteria, While satisfying the further criteria set forth herein, notonly is it possible to produce a system in which deposit of thedispersed wall-forming entities around the dispersed core entities canbe achieved, but also this can be done with core materials that couldnot before be successfully encapsulated by any en masse process using aliquid manufacturing vehicle.

The further criteria which define the useful classes of materials forthe core material, vehicle and wall-forming solution are these: (1) thepolymeric material of the wall-forming solution should be capable ofdissolving in the particular non-aqueous liquid chosen; (2) the solutionof polymeric materials which form the capsule wall must be capable ofwetting the core material in order to deposit around the core entities,and, with regard to wetting properties, the polymeric wall materialpreferably should have naturally-occurring or artificially suppliedwetting groups such as COOH; OH; -COOR; CN; Cl; and F, the wettingproperties of which in certain instances may be enhanced by the liquidin which it is dissolved; (3) the solution of polymeric material shouldhave a viscosity such that it may both deposit itself and also maintainitself deposited around the core entities despite the shearing forces ofthe agitation needed to maintain the dispersion; (4) the solution ofpolymeric material should constitute such a percentage of the totalthree-phase system, by volume, that it can exist as a dispersed phase ofmobile entities capable of deposit around the core entities; and (5) thecore material, the solution of polymeric material (coacervate phase),and the vehicle must be mutually incompatible.

The wetting action of polymeric materials in solution as regards aparticular core material may be measured by standard contact-anglemeasurements, adsorption measurements, and the like, and suitableselections may be made thereby, all in accordance with existingknowledge of this subject per se. The solvent for the polymeric materialmay in certain instances be selected to enhance the wetting action of aparticular polymeric material solution with respect to a chosen corematerial. If a solvent is chosen that is too good a solvent for aparticular polymer, which inhibits its wetting action with respect tothe core material, then a higher molecular weight of the polymer may beused to reduce the solubility of the solvent used, or else a poorersolvent is substituted.

The term non-aqueous as used in the specification and claims does notexclude liquids having small amounts of water, provided, however, thatthe amount of water in the non-aqueous liquid is such that thecompatibility or incompatibility of the liquid relative to the othermaterials in the capsule-forming system is not substantially altered.

The stated criterion that the core material, the coacervate solution ofpolymeric material, and the vehicle be mutually incompatible is used inthe sense that their separate existence in the system must not beimpaired by any reactivity or miscibility between them.

Prefabricated incomplete systems for use in carrying out the novelprocess may be established and stored for future use. Even unskilledoperators may complete such systems by the addition of the missingcomponents, with the required agitation, and heat if necessary, togetherwith agents for hardening of the Walls, to make capsules at a latertime. The missing component(s) may involve any of those three necessaryfor forming an operative system, and the absence may be total orpartial.

The preferred system is one in which the non-aqueous liquid used as thesolvent for the wall-forming polymeric material also serves as the majorcomponent of the manufacturing vehicle. The vehicle then must containanother material, in solution in it, which is complementary to thewall-forming material in the sense that it creates an incompatibilitybetween the vehicle and the wall-forming polymeric material and inducesand/or maintains as a separate liquid phase, a Wall-forming solution ofthe polymeric material. Alternatively, instead of or in conjunction Withanother complementary material, the entire system may be subjected to acondition which will act to or assist in inducing and or maintaining theincompatibility between the vehicle and the solution of wall-formingpolymeric material. In other words, the complementary material orcondition completes a liquid system in which the suitably-viscous,wall-forming non-aqueous solution of polymeric material can exist as aseparate phase dispersed in the vehicle because of repulsive forcesbetween the polymeric material of the wall-forming nonaqueous solutionand the complementary material and/or condition. Without thecomplementary material and/or condition, if the vehicle included orconsisted of the same liquid that is used as the solvent for thewall-forming polymer, the vehicle would be miscible with and woulddilute the polymer solution, which polymer solution then would not existas a separate phase of proper viscosity.

Viewing the core material as the guide to the selection of the polymericwall-forming material and its solvent, and also to the selection of theliquid vehicle if that is not to consist of or include as a solvent thesame material that is used as the wall-forming polymer solvent, thepolymeric material and its solvent must be incompatible with the corematerial, but capable of wetting and depositing around entities of it;and the polymeric material of the wall-forming non-aqueous solution mustbe compatible with the liquid that is to form the component of theseparated or coacervate phase. When, as preferred, the vehicle is madeup chiefly or wholly of the same material as the liquid of thewall-forming polymer solution, the only further choice is with respectto the complementary material and/or condition, which, again, must meetthe incompatibility requirement. The complementary material and/orcondition must be incompatible with the core material and must act tomake it possible for the wall-forming polymeric material solution toexist as a separate phase.

Given these criteria of selection, not known before in total, as thedeterminants of an operative encapsulation system, the classes ofmaterial that are useful in constituting the vehicle and thewall-forming polymer solution of the present system are ascertainablefrom existing knowledge and means of selection of polymeric materialsand solvents in respect of three properties; viz.:

(1) Solubility of the polymer in various non-aqueous solvents;

(2) ,Ability of the polymer solution to wet the given core material,liquid or solid; and

(3) Ability to exist in separate solution phase in the vehicle liquid.

Materials thus selected are useful in the encapsulation of anyincompatible and wettable core material, liquid or solid.

Polymeric material suitable for use in the process of the presentinvention include synthetic and natural macromolecular polymers such as,for example, polystyrene, cellulose acetate, polyvinyl acetate,polyvinyl alcohol, polyvinyl chloride, dinitrocellulose,trinitrocelluose, cellulose acetobutyrate, benzyl cellulose, and rubber.Additional suitable macromolecular polymers are those of the polybasictype-for example, deacetylated chitin, polyvinyl pyridine, styrene-vinylpyridine copolymer, and polymeric quaternary ammonium saltsand those ofthe polyamide type-for example, polylysine, polyornithine,poly-p-amino-phenylaniline, and polyacrylamide.

Another class of suitable polymeric material is made up ofmacromolecular synthetic polymers having an average molecular weight ofat least 20,000 and having a linear, as opposed to a cross-linked,polymeric structure for example, those whose polymer units comprise bothlipophilic and hydrophilic units; i.e., one class of recurring polymerunit is essentially lipophilic in character (for example, one derivedfrom styrene, an alkyl ring substitute styrene, an ether or estersubstituted ethylene), and the other major recurring unit is essentiallyhydrophilic in character (for example, derived from maleic acid, maleicacid amide, acrylic acid, crotonic acid, acrylic acid amide). Incombination, these lipophilic and hydrophilic units preferably comprisea majority of the polymeric units present in the copolymer. Otherpolymer units may also be present in the copolymer, so long as they arepresent in minor amounts; that is, less than either the hydrophilic orthe lipophilic polymer units. Included among these polymers are thehydrolyzed styrene-maleic anhydride copolymers, styrene-maleic acidamide copolymers, the sulfonated polystyrenes, polymethacrylic acid, andmethyl vinyl ether-maleic acid copolymer.

Additional suitable polymeric materials are the carbohydrate acetatephthalates (e.g., starch acetate phthalate, cellulose acetate phthalate,and amylose acetate phthalate).

Among the preferred synthetic polymers employed in this invention arethe hydrolyzed styrene-maleic anhydride copolymers, the anhydride groupsof which are preferably at least 50% hydrolyzed. The copolymer can alsocontain other polymer units in minor amounts; e.g., those derived fromacrylonitrile, acrylic acid, methacrylic acid, itaconic acid, vinyl,ethyl vinyl ether, methyl vinyl ether, vinyl chloride, vinylidenechloride, etc., and the like. As used in the present specification, theterm hydrolyzed styrene-maleic anhydride copolymer is meant to includethese modifications as well as other modifications in the structure andmethod of preparation which do not alter the essential lipophilic andhydrophilic properties of the copolymer. The preferred polymericmaterial can be represented by the following formula:

wherein R represents lipophilic polymer units of which more than 70% arestyrene residues, the remainder, when present, being residues of otherethylenic monomers, for example, of acrylonitrile, acrylic acid,methacrylic acid, itaconic acid, vinyl chloride, vinylidene chloride,and the like; and R represents hydrophilic polymer units of which morethan 50% are maleic acid residues, preferably more than 70% with theratio of R to R being from 1:1 to about 4:1, preferably from about 1:1to about 12:1, and n is an integer from about to about 1000. The averagemolecular weight of the copolymer ranges preferably from about 20,000 toabout 200,000. Styrene-maleic anhydride copolymer, which is readilyhydrolyzable to styrenemaleic acid copolymer, is a commerciallyavailable styrene-maleic anhydride copolymer which may be modified orunmodified. This copolymer can be hydrolyzed to obtain a styrene-maleicacid copolymer which is useful in the present invention. The hydrolysiscan be partial or complete and involves a conversion of the acidanhydride linkages to ot-dicarboxylic acid units. It is preferred thatthe hydrolysis be substantially complete; i.e., more than about 50%complete.

Garrett and Guile (I. Am. Chem. Soc., 73, 4533 (1951)) have shown that,in the polymerization of styrene and maleic anhydride, for a 1:1 molarreactant ratio (styrene (R):maleic anhydride (R)), the molar ratio ofmonomeric units in the polymer (R:R') was 1.124; for a 3:1 molarreactant ratio (R:R') the molar ratio of monomeric units in the polymer(R:R') was 1.183; for a 1:3 molar reactant ratio (R:R'), the molar ratioof monomeric units in the polymer (R:R') was Between pH 1 and 2.5 (thepH found in the normal stomach), a styrene-maleic acid copolymer asdefined herein is only 0 to 1% ionized and thus is insoluble at this pH,making this copolymer a useful enteric coating for oral pharmaceuticalproducts whose active ingredient is most efiicaciously utilized whenabsorbed in the intestines rather than the stomach.

While the invention has been discussed and exemplified in terms of asingle polymeric material as the principal component of the coacervatephase, the invention is not so restricted and it is within the intendedscope of this invention to include mixtures of polymers in thecoacervate phase, or in the vehicle, so long as the criteria set forthherein are maintained.

7 Non-aqueous liquid systems suitable for the separation of amacromolecular polymer-rich liquid phase are, illustratively, thefollowing:

Miseible, non-solvent Phase forming polymer First liquid liquidPolyvinyl chloride Cyclohexane Glycol. Cellulose acetobutyrate Methylethyl ketone Isopropyl ether. Benzyl cellulose TrichloroethylenePropanol. Polyethylene Xylene Amyl chloride. Sty'rene-maleic acidEthanol, methanol Ethyl acetate, methyl copolymer. ethyl ketone butylethyl ketone lsopropyl ether. Rubber Benzene Methanol}, propanol,glycol,

g cero Polyvinyl acetate Ohloroform Ethanol Methanol Butano] Ethylcellulose Xylene methanol n-Hexane.

ADDITIONAL WALL-FORMING POLYMERIC CORE MATERIALS MATERIALS Sodiumamobarbitol (A) Ethyl cellulose (preferably one having an ethoxylcontent of about 47.5 by weight and a viscosity of 22 centipoises in aconcentration, by weight, in an 80/ toluene-ethanol bath at degreescentigrade).

(B) Cellulose nitrate (preferably of 11.8% to 12.2% nitrogen content).

(C) Cellulose acetate phthalate (preferably of to esterified phthaloyland of 17% to 22% esterified acetyl content).

(D) Polymethyl methacrylate (about 100,000 to 150,000 molecular weightby viscometric measurement).

(E) Acrylonitrile-styrene copolymer (about 15/ 85- by Weight).

(F) Polystyrene (about 80,000 to 100,000 molecular weight by viscometricmeasurement).

(G) Vinylidene chloride-acrylonitrile copolymer (a) 78.8%/21.2% or(b)--90.2%/9.8%.

(H) Epoxy resin (viscosity of 100-160 poises at 25 degrees centigrade,epoxide equivalent l75218).

(I Polyvinyl-formal (preferred 30,000 molecular weight, hydroxyl contentexpressed as percent, polyvinyl alcohol 5-7; and acetate contentexpressed as 25% polyvinyl acetate).

SOLVENTS (I) Toluene-ethanol (II) Methyl ethyl ketone (III)Toluene-ethanol-ethyl acetate (IV) Acetone (V) Benzene (VI) Toluene(VII) Nitropropane (VIII) Dioxane (IX) Tetrahydro-naphthaleneCOMPLEMENTARY SUBSTANCES FOR INDUCING PHASE SEPARATION (K) Petroleumdistillate, boiling point 35 to 70 degrees Centigrade.

(L) Polybutadiene, 8,000 to 10,000 molecular weight as determined by theosmotic pressure method.

(M) Polydimethyl-siloxane, 500 centistokes viscosity.

(N) Ethanol.

O) Phenol-methyl siloxane, 475 to 525 centistokes viscosity.

(P) Methacrylic polymer, viscosity 325 centistokes in low-viscositypetroleum distillate.

THREE-PHASE SYSTEMS (Symbols as above) Penicillin acid Ascorbic acidPolyvinyl pyrrolidone Acetyl p-amino phenol Bacillus thuringiensis LeadTitanium dioxide Zirconium hydride Iron Zinc Calcium hydrideTetracyclines Sodium chloride Phthalic anhydride Magnesium hydrideAmmonium dichromate Sodium bicarbonate Stannous fluoride Sodium acidpyrophosphate Quinine sulfate Aspirin Methylene blue Vanillin Quinidinegluconate Dichlorocyanuric acid Trichlorocyanuric acid Potassiumpenicillin d-propoxyphene hydrochloride d-desoxyephedrine hydrochlorideSulfamerazine Crystal violet Pepsin enzyme Riboflavin Thiamine chlorideQuinidine sulfate Albumin Pancreatin Bacitracin Aluminum aspirin Calciumsalicylate Gelatin Gum arabic Methyl cellulose Carboxymethyl celluloseCellulose acetate phthalate Starches Sucrose Mannitol Potassium chloridePotassium iodide Citric acid In its broader aspect, the invention is notin the discovery of particular polymers or solvents or vehicles butrests on and applies the discovery that liquid and solid nucleusmaterials, including materials compatible with Water, can beencapsulated in a system wherein the liquid associated with thewall-forming polymer in the wallforming polymer solution is non-aqueousand which comprises the combination of three separate phases of therespective kinds here defined. It is the combination of the three ratherthan the particular substances used in any one that is the basicinvention.

In a narrower aspect, the invention includes a particular procedure forestablishing the defined system. This particular procedure involves theformation of a system comprising a wall-forming polymeric material andat least two liquids, said liquids being miscible with each other and atleast one of the liquids being incompatible with the wall-formingpolymeric material; the polymeric material being the intended wallformer, and a separation of this system into two separate solutionphases, one being the polymeric wall-forming material and associatedliquid (coacervate phase) and the other being the equilibrium liquid.The polymeric material and the liquids may be assembled in any order toeffect the phase separation, but it is preferable first to form a dilutesolution of the polymeric material that is intended to be in thewall-forming phase, and then to induce phase separation by the additionof a second liquid miscible with the first liquid but incompatible withthe wall-forming polymer, the role of the secondary liquid being toinduce and maintain the phase separation. The addition of the secondarycomplementary liquid to an initial dilute solution of the wallformingpolymeric material permits easier control of the phase separation toyield a wall-forming solution phase of suitable viscosity and volume,especially in an initial operation before the procedure is standardizedquantitatively for any particular polymeric material and liquids. Insuch an initial operation, and by any technique of establishing thethree phases as described herein, the attainment of the desiredviscosity in the wall-forming solution phase may be ascertained bymicroscopic observation of an agitated sample of the system containingdispersed core material, the criterion being that, when a usefulwallforming solution is present, it is seen that the discrete entitieswith liquid walls are formed. A confirmation and basis for quantitativestatement can be had by allowing the two separated solution phases tostratify and then measuring the viscosity and relative volume of thephase containing the intended wall-forming polymeric material. If theviscosity is too low, addition of more of the complementary materialwill cause additional concentration of the wall-forming phase to occur,with a consequent increase of viscosity of that phase, until the desiredviscosity is attained.

The proper volume relation of the wall-forming phase (of properviscosity) can be predetermined to a close enough approximation bycalculation from readily-ascertained data on the relation of viscosityto concentration for a solution of the intended wall-forming polymer inthe chosen solvent.

The order of addition can be reversed, or the polymeric material and theliquids can be brought together at one time, once the properquantitative relations are established for the particular materialsbeing used. However, experience has shown that in the case Where thecomplementary material is a non-solvent for the wall-forming polymerthat the non-solvent should be added gradually for the best results.

The core material, always a minor component of the total volume of thesystem, can be added either before, during or after the formation of thewall-forming solution of polymeric material. Similarly, the agitation ofthe system can be begun before, during, or after either of these steps.It is preferred, however, to agitate before, during, and after the phaseseparation.

The intensity of the agitation is made such as to reduce the corematerial to the desired entity size, if such is necessary, and, in anyevent, to assure thorough dispersion of it in the vehicle. The coreentity size is pre-selected to give the desired capsule size afterallowance for encapsulating wall thickness. With solid core materials,the

entity size can be predetermined and obtained by suitable grinding ormilling, or other means known in the art.

An alternative way of establishing a three-phase system, consisting of acontinuous vehicle, a dispersed nucleus phase, and a dispersedwall-forming solution phase, involves forming a system comprising twodiiferent polymeric materials and a common solvent, one polymericmaterial being the intended wall former, and a separation of this systeminto two separate solution phases, one containing chiefly the otherpolymeric material, by a phenomenon of phase separation known in itselffrom the work of Dobry and Boyer-Kawenski, published in the Journal ofPolymer Science, volume 2, No. 1, pages to (1947), but not before knownto be useful in a system of encapsulation. The two polymeric materialsand the solvent may be assembled in any order to effect the phaseseparation, but it is preferable first to form a dilute solution of thepolymeric material that is intended to be in the wall-forming phase, andthen to induce the phase separation by addition of the second, orcomplementary, polymeric material, the role of which is to induce andmaintain the phase separation.

The second polymeric material in that case is one that has either noaffinity or a lesser affinity for the core material, so that thesolution of the first polymeric material (the intened wall former) willbe the one that preferentially deposits around the dispersed coreentities. This second polymeric material is referred to as acomplementary polymeric material.

The addition of the complementary polymeric material to an initialdilute solution of the wall-forming polymeric material permits easiercontrol of the phase separation to yield a wall-forming solution phaseof the proper viscosity and relative volume, especially. in an initialoperation before the procedure is standardized quantitatively for anyparticular polymeric materials and common solvent.

The order of addition can be reversed, or the two polymeric materialsand the solvent can be brought together at one time, once the properquantitative relations are established for the particular materialsbeing used, since the resulting volume and viscosity (concentration) ofthe two separate phases are independent of the order of assembly.

By reason of the discovery of Thomas C. Powell et al. described in US.patent application Ser. No. 192,070, filed May 3, 1962, and nowabandoned, that polymeric materials having one or more groups from theclass consisting of hydroxyl, carboxyl, the ester COOR (where R is analkyl of up to four carbon atoms), cyano, chlorine, or fluorine groupsare capable, when in solution, of wetting water and water-like corematerials, and of depositing around them to form capsules by the basicprocess of the present invention, such polymeric materials are withinthe class of wall forming materials useful in the present invention.When such polymeric materials are used, the conditions in other respectsare those created by the present invention, and this discovery of asub-class of polymeric materials which can wet and encapsulate aqueousliquid core material therefore satisfies that condition of the processof this invention with respect to the polymer material of thewall-forming solution and makes its use a specific instance of use ofthe present invention.

Polymeric solutions which meet the requirement of incompatibility withthe vehicle are known from the study of Dobry et al., cited above,concerning the incompatibility of different polymers when in solution ina common solvent, whereby separation into two solution phases occurswhen ot impeded by excessive viscosity of the system. That impedingviscosity does not exist under the conditions here defined with respectto the viscosity and volumetric proportion of the wall-forming polymersolution as a component of the present three-phase system.

Thus, where another polymeric material is used as the complementaryincompatibilizing material in a system in which the same liquid is usedas the solvent for the wallforming polymeric material and as the majorliquid component of the vehicle, the polymeric material used in thewall-forming solution may be any polymer that has a greater afiinity forthe core material than does the polymer serving as the complementarymaterial, so that the wall-forming polymeric material will depositpreferentially around the core entities.

When the three-phase capsule-forming system is established by thepresence of a complementary polymeric material, the continuous orvehicle phase consists of a more dilute and less viscous solutioncontaining the greater part of the complementary polymeric material; andthat polymeric material is the material which imparts the necessaryincompatibility between the vehicle and the wallforming solution phaseand permits the latter to exist as a separate dispersed phase. The smallamount of complementary polymeric material that may pass into theseprated wall-forming solution phase by entrainment or otherwise is notobjectionable.

Another alternative procedure is to pre-form a solution of wall-formingpolymeric material having the desired viscosity, and then to disperse itin a vehicle which is a liquid that is immiscible with this polymericmaterial solution and with the core material. This avoids any phaseseparation step such as is necessary when the wall-forming polymericmaterial is initially present in dilute solution and has to be drivenout in a more concentrated solution as a separate phase having thedesired viscosity, whether by reason of a complementary other polymericmaterial or by reason of a complementary non-solvent for thewall-forming polymer, or other means.

The temperature of the system is dictated by the nature of thecomponents. In the instance where the wall-forming polymeric materialsets on cooling, the mass should be maintained above the settingtemperature duringthe wrapping step. Moreover, the upper temperaturelimit is determined by the stability of the components at elevatedtemperatures and further by the respective boiling points. It ispreferred to conduct the wrapping and subsequent steps at a temperaturebelow the boiling polnt of any of the components.

The ratio of macromolecular polymer to the liquid or solid core materialto be coated is varied with the thickness of the coating desired.

In order to obtain a desired coat thickness, the ratio of the amount ofmacromolecular polymer to the amount of the core material to be coatedvaries with the total surface area of the core material. Thus, forlarger surface areas, controlled by the degree of dispersion in the caseof liquid core material, and by a prior reduction in size in the case ofsolid core material, the amount of macromolecular polymer is increased.

Although it is preferred that the liquid and solid core material forcoating by phase separation be insoluble, the coating of core materialwith some or appreciable solubility is not outside the concept of thepresent invention. For example, core material with some solubility inthe first liquid can be rendered insoluble, by the addition of thesecond liquid, prior to the formation of the coacervate or wall-formingphase.

The setting of the liquid phase about the core material to render theliquid phase immobile can be accomplished in various manners.Illustrative, but not limiting, are cooling in the case of a gelablepolymeric material, raising the pH in the case of a :polybasic polymer,reducing the pH in the case of an acidic polymer, reacting acidic groupswith a divalent or multivalent ion-for example, Ca++, Mg++, Fe++, Fe+++,or Al+++modification of the coat by the addition of a monomer andmodication by the utilization of an additional non-solvent.

The further setting or hardening of the coat to prevent reversibility ofthe phase separation, as desired, can be carried out by utilizingvarious methods. Illustrative thereof are the addition of dicarbonylcompounds, alum, tannic acid, and tannic acid and ferric chloride, theremoval of occluded liquid by drying and/or heating; changes in pH; andthe use of the Van de Graaif sterilizer for irradiation; it being withinthe skill of the art, after having the benefit of this disclosure, toadapt specific techniques to the nature of the wall-forming polymericmaterial.

The removal of the vehicle liquid and the separation of the coated corematerial thereby are preferably carried out prior to the washing of thecoated particles. Said separation is preferably accomplished bycentrifugation; however, filtration and decantation can be employed. Inthe case of washing, in situ, the separation of the coated core materialcan be carried out by spray-drying.

For washing the coated core material, at the centrifuge or duringfiltration, a non-solvent for the wall-forming polymer may be used andin the case where a non-solvent was employed to effect the formation ofthe wall-forming polymer solution additional amounts of the non-solventsecond liquid may be used. The liquid Wash removes traces of the vehicleliquid and puts the coated core material in condition for drying.

The drying of the coated core material may be carried out by simpleevaporation, in vacuo, or by the application of heat, depending on thenature of the mass.

The process of the present invention possesses utility in providingcoatings that (1) protect the coated liquid or solid core material fromoxidative degeneration, (2) prevent contact between incompatiblesubstances in a mixture of ingredients, (3) mask undesirable odors andtastes, (4) provide a barrier to release of the coated liquid or solidcore material until the desired pressure is appiled to rupture the coat,(5 provide controlled release of the coated material in various mediasuch as the stomach and the intestine, (6) provide increased stabiiltyof the coated material, and (7) provide a coating permitting thehandling of corrosive and/or irritating materials.

The following examples are for the purpose of illustration and to setforth the best mode contemplated by the application of carrying out hisinvention. They are not to be construed as limiting.

EXAMPLE 1 phase) separates and coats the phosphate compound. The

Whole mixture is cooled to room temperature. Thereafter, the coatedparticles are separated, advantageously by centrifuging, thoroughlywashed with isopropyl ether, and allowed to dry. A capsule having apowdery phosphate compound as the core material is thereby obtainedwhich is suitable for use as a slow-release fertilizer.

EXAMPLE 2 A solution of 10 grams of benzyl cellulose is prepared atabout 40 degrees centigrade in 300 milliliters of trichloroethylene.grams of sodium (2,4-dichlorophenoxy) acetate is added to this systemwith adequate stirring. With stirring and with the temperaturemaintained at about 40 degrees centigrade, propanol is added. When theconcentration of propanol reaches about 51%, v./v., a benzylcellulose-rich liquid phase separation occurs, and the sodium(2,4-dichlorophenoxy) acetate is coated by the separating phase. TheWhole mixture is cooled to room temperature. Thereafter, the coatedmaterial is separated, by centrifuging, thoroughly washed with propanol,and allowed to dry. A capsule comprising a benzyl cellulose-coated asthe wall material and powdery acetate as the interior material isobtained which is suitable for use in slow-release weed control.

EXAMPLE 3 A macromolecular solution is prepared with 25 grams ofstyrene-maleic acid copolymer and 25 milliliters of ethanol at about 50degrees centigrade. 25 grams of morphine monohydrate is dispersedtherein. Ethyl acetate is slowly added to the whole mixture withadequate stirring. When the concentration of ethyl acetate reaches about74%, v./v., a copolymer-rich liquid phase separation occurs, which coatsthe dispersed morphine monohydrate. Thereafter, the coated morphinecompound is recovered, washed with ethyl acetate, and alloyed to dry.The soobtained coated morphine compound is suitable for use in aqueoussuspensions.

EXAMPLE 4 A macromolecular solution is prepared with 100 grams ofstyrene-maleic acid copolymer and 100 milliliters of methanol. 800 gramsof pancreatin is dispersed therein. Butylethyl ketone is added to thewhole mixture with adequate stirring. At a relative concentration of 60%of the ketone, v./v., a copolymer-rich liquid phase separation occurs,which coats the pancreatin. Thereafter, the coated pancreatin isrecovered, washed with more of the ketone, and dried. The so-coatedpancreatin is protected from the destructive acidic action of thestomach juices after oral ingestion.

EXAMPLE 6 A macromolecular solution is prepared from 70' grams ofstyrene-maleic acid copolymer in 700 milliliters of ethanol at 50degrees centigrade. 17 grams of tribasic sodium phosphate is dispersedtherein. With constant stirring, butylethyl ketone is slowly added to aconcentration of 60%, v./v., to cause separation of a liquidcopolymer-rich liquid phase. The so-separated phase coats the phosphatecompound, which is thereafter recovered, washed with butylethyl ketone,and allowed to dry. The coated phosphate compound can be handled withoutthe corrosive and irritating action of the uncoated compound and issuitable, for example, as a drain cleaner.

EXAMPLE 7 A macromolecular solution is prepared from 100 grams ofstyrene-maleic acid copolymer in 1000 milliliters of methanol. 25 gramsof methylsilicone oil is dispersed therein at about 50 degreescentigrade. With constant stirring, isopropyl ether is slowly addeduntil the ether concentration reaches 47%, v./v. A liquid copolymer-richliquid phase separates and coats the dispersed oil. Thereafter, thecoated oil is recovered, washed with isopropyl ether, and allowed todry. The thus-coated oil is useful as a lubricating grease.

EXAMPLE 8 An ethylcellulose-coated water-soluble dye is prepared andcoated in the following manner:

grams of ethylcellulose is dissolved in a mixture of 100 milliliters ofxylene and 20 milliliters of ethanol. One-half gram of alizarine cyaninedye is dispersed in the solution. 125 milliliters of n-hexane(Skellysolve B) is 14 added drop by drop to separate anethylcellulose-rich liquid phase, which coats the green dye. The coateddye particles are separated by filtration, washed with n-hexane, andvacuum dried.

A solution of 5 grams of cellulose acetobutyrate is prepared in 100milliliters of methylethyl ketone. The abovecoated dye particles aredispersed in this solution at about 40 degrees centigrade. With constantstirring, isopropyl ether is added to a concentration of 42%, causingthe separation of a cellulose acetobutyrate-rich liquid phase. Saidliquid phase forms an additional coat on the ethylcellulose pre-coateddye particles. The double-coated particles are recovered bycentrifugation, washed with isopropyl ether, and dried at about 30degrees centigrade.

EXAMPLE 9 A solution of 100 grams of gelatin in 900 milliliters of wateris prepared at 45 degrees centigrade. Eight grams of oil of rose isdispersed in this solution, with adequate stirring to maintain the oilthoroughly and uniformly mixed. With stirring and with the temperaturemaintained at 45 degrees centigrade, ethyl alcohol is added to thedispersion. It is preferred to use a denatured alcohol; for example, oneof the commercial denatured ethyl alcohols containing a minor amount ofmethanol. The methyl alcohol is added slowly with stirring. When theconcentration of ethanol reaches about 50%, v./v., a gelatin-rich liquidphase separates and coats the dispersed oil. When the ethanolconcentration reaches about 55%, v./v., the whole mixture is cooled toabout 5 degrees centigrade to set the coating. The coated oil isseparated from the bulk of the residual liquid by centrifugation.Thereafter, the coated oil is washed thoroughly with ethanol and allowedto dry in vacuo at 25 degrees centigrade.

2.5 grams of the gelatin-coated particles are dispersed at 50 degreescentigrade in a solution of 10 grams of styrene-maleic acid copolymer in100 milliliters of ethanol. With adequate stirring, butylethyl ketone isadded to a concentration of 60%. A copolymer liquid phase separates andsuperimposes a second coat on the gelatin-coated oil of rose. The pH ofthe whole mixture is lowered to pH .1.0 to set the copolymer coat.Thereafter, the doublecoated oil of rose particles are recovered bycentrifugation, washed with butylethyl ketone, and dried at roomtemperature.

EXAMPLE 10 15 milliliters of a 0.5% w./v. aqueous solution of amaranth(F.D. & C. No. 2) is added with vigorous agitation to milliliters of a5.0%, W./v., solution of cellulose acetate butyrate in methylethylketone. This mixture is then passed through a hand homogenizer threetimes. Enough additional butyrate solution is added to the homogenizerto make 15 0 milliliters of emulsion.

The emulsion is then heated to 55 degrees centigrade on a steam bathwhile being stirred rapidly. An additional 15 milliliters of amaranthsolution is added at this time.

To the emulsion system, isopropyl ether, previously heated to 50 degreescentigrade, is added in small portions with agitation. An increasedcloudiness is noted when milliliters had been added. The presence ofliquid phase-coated water droplets can be confirmed by microscopicexamination.

Thereafter an additional 10 milliliters of isopropyl ether is added withstirring to produce further separation of liquid phase. The mixture isallowed to cool slowly without agitation. The coated particles areseparated by centrifugation, washed with isopropyl ether, and dried invacuo.

EXAMPLE 11 In this example, there will be considered the encapsulationof ammonium nitrate particles in ethyl cellulose, the whole processbeing carried on in a ZOO-milliliter beaker at 25 to 50 degreescentigrade, with the materials being agitated constantly. There isintroduced into the beaker 50 grams of a 2%, by weight, solution ofethyl cellulose in an 80/ 20 toluene-ethanol solvent, the particularethyl cellulose having a viscosity grade of 22 centipoises, and anethoxyl content of 47.5%, by weight, the viscosity being determined whenthe ethyl cellulose is dispersed dry in a concentration, by weight, inan 80/ toluene-ethanol bath at degrees centigrade. Into the ethylcellulose is introduced 40 grams of ammonium nitrate particles whichhave a ZOO-micron average dimension, followed by the introduction of 25grams of polybutadiene having a molecular weight of 8000 to 10,000 asdetermined by the osmotic pressure method, said butadiene being a liquidand introduced over a period of fifteen to thirty minutes, during whichtime a coacervate phase comprising a solution of ethyl celluloseseparates from the rest of the system as small liquid entities whichdeposit on and surround each ammonium nitrate particle individually,such being brought about mechanically by the agitation and chemically bythe wetting substituent groups of the ethyl cellulose. The phaseseparation of the ethyl cellulose as a liquid includes the carrying withit of a part of its original solvent, and in this particular examplesuch mostly consists of the ethanol component and a small part of thetoluene component. The liquid deposits are hardened by introducing intothe system, after the liquid walls have been formed, 15 grams of toluenediisocyanate over a period of a minute or two, the toluene diisocyanateseemingly combining with the ethanol of the deposited wall material,forming plasticized self-supporting firm ethyl cellulose walls which aresubstantially water-impermeable.

Water-sensitivity of the core material is not a requirement necessaryfor the practice of the invention, as materials not sensitive to watermay be encapsulated thereby.

The finished capsules may be recovered from their liquid environment anddried for their end use, one of such uses being to act as core entitiesto receive a second wall of the same material or another materialapplied by the method of this invention or by any other en masse method,or by coating, spraying, or rolling.

EXAMPLE 12 To 196 grams of toluene add 4 grams of ethyl cellulose, asspecified in Example 11, and stir at 25 degrees centigrade until a clearsolution is formed. Disperse therein 16 grams of the desired corematerial reduced to any desired particle size between 40 and 5,000microns, and, with agitation, slowly add, over a period of fifteenminutes, '40 grams of polybutadiene of 8,000 to 10,000 molecular weight,as obtained by the osmotic pressure method, which addition induces phaseseparation of the ethyl cellulose in solution of proper viscosity andthe encapsulation of the core particles with it. The capsule walls maybe hardened by the addition to the agitated system of 0.2 gram oftetrabutyl titanate.

EXAMPLE 13 To 196 grams of carbon tetrachloride add 4 grams of ethylcellulose, as specified in Example 11, and stir until there is a clearsolution at 25 degrees centigrade, thereafter dispersing in the solution16 grams of the selected core material (for example, aspirin) dividedinto the desired particle entity size. Add 120 grams of mineral spiritshaving a boiling point of 130 degrees to 190 degrees centigrade, tocause phase separation of the viscous ethyl cellulose solution and itsdeposit on the core entities. The walls of the resulting embryoniccapsules then may be hardened with tetrabutyl titanate, as has beendescribed in Example 12.

EXAMPLE 14 Prepare a solution of 4 grams of ethyl cellulose, asspecified in Example 11, in 196 grams of cyclohexane, stirring at 80degrees centigrade. Add 16 grams of particles of intended core material(iron powder, for example), and, with continued agitation, add, over aperiod of five minutes, 20 grams of polybutadiene, as specified 16 inExample 12, during which the system is allowed to cool to 50 degreescentigrade. The further cooling to room temperature, with stirring,results in a hardening of the capsule walls.

EXAMPLE 15 Stir 4 grams of cellulose nitrate (11.8% to 12.2% nitrogencontent) into 196 grams of methyl ethyl ketone at 25 degrees centigradeuntil a clear solution is formed, and then add 4 grams of theparticulate intended core material (for example, titanium dioxide). Tothe stillbeing-stirred solution add 50 grams of the polybutadienespecified in Example 14 to form liquid-walled embryonic capsules. Thecapsule walls are hardened by stirring in 0.2 gram of tetrabutyltitanate.

EXAMPLE 16 Make a solution of 10 grams of vinylidenechlorideaerylonitrile copolymer, having a component ratio of 78.8/21.2,in 196 grams of tetrahydrofuran at 25 degrees centigrade until a clearsolution is formed. Stir in 16 grams of the selected core materialparticles, and, with agitation, add 30 grams of polybutadiene of 8,000to 10,000 molecular weight specified in Example 12, to cause a polymerphase separation and the deposit of it on the core particles. Thecapsule walls may be hardened by the addition of tetrabutyl titanate inan amount of 0.4 gram with stirring. 4

EXAMPLE 17 Add 10 grams of cellulose acetate phthalate (preferably of30% to 40% esterified phthaloyl and 17% to 22% acetyl content) to 190grams of dioxane at 25 degrees centigrade to form a clear solution. Tothis is added, as exemplary coloring material, 20 grams of ammoniumdichromate having a particle size of 250 to 800 microns. With agitation,add 72 grams of polybutadiene of 8,000 to 10,000 molecular weight asdetermined by the osmotic pressure method, which addition, withcontinued agitation, forms capsules with liquid walls which may behardened by extraction of the solvent with petroleum distillate.

EXAMPLE 18 In this example, water-sensitive materials are encapsulatedin ethyl cellulose by forming a three-phase system of a liquid vehicle,the capsule wall-forming ethyl cellulose in solution, and particles ofintended core material, the separate phase of the ethyl cellulose beingbrought about by introduction, into the vehicle in which it wasdissolved, of a non-polymeric liquid which is preferentially soluble inthe vehicle. More specifically, a roomtemperature solution of 36 gramsof toluene, 9 grams of ethanol, and 5 grams of the ethyl cellulosespecified in Example 11 is formed, and with agitation, 5 grams offinely-divided ammonium dichromate is dispersed therein. The temperatureof the system is raised to 70 degrees centigrade, and, still withagitation, 40 grams of petroleum distillate (boiling point slightlyabove 70 degrees centigrade) is added slowly, as by pipette, over aperiod of ten to fifteen minutes. This causes separation of a denseethyl cellulose solution of the required wall-forming viscosity, thesolvent being mostly of the ethanol part of the vehicle, as a dispersedliquid phase which deposits on the ammonium dichromate particles. Thisdeposited material is robbed of its solvent by the addition of morepetroleum distillate (about grams) after the system has been reduced toroom temperature. The walls of the capsules then are firm, and thecapsules may be recovered from the liquid vehicle and dried to afree-flowing powder.

EXAMPLE 19 This is the same process as Example 18 except that polymethylmethacrylate (of about 100,000 molecular weight by viscometricmeasurement) may be used in place of ethyl cellulose, and methyl ethylketone or benzene may be used as the solvent in place of the toluene- 17ethanol solvent, the same proportions of materials being used. Eitherpetroleum distillate or hexane may be used as thephase-separation-inducing material.

EXAMPLE 20 This process, particularly adapted to the encapsulation ofaqueous solutions, is begun by introducing into a 500- milliliterbeaker, at room temperature, 100 grams of a by weight, solution of aspecially-modified copolymeric material having the general structurepolyvinyl polyvinyl polyvinyl chloride alcohol acetate H H H H H H I l II H H r" H Cl 191% (51 $11 y6% H (l dissolved in ethylene chloride.Next, 10 grams of a 10%, by weight, solution of sodium ferrocyanide inwater is introduced, with agitation to reduce it to the desired dropsize, to furnish the capsule core material ingredient. This preferredcore material is exemplary of a colorless water solution of a colorreactant. To the agitated mixture (which may be termed a water-in-oilemulsion) is added slowly, as a phase-separation-inducing polymericmaterial, grams of polydimethyl siloxane, of for instance, 500centistoke viscosity, the addition preferably being made drop by dropover a period of three or four minutes to prevent agglomeration of themodified polyvinyl chloride wall-forming material as it separates out,thus permitting it to break up into small entities which deposit evenlyover the droplets of nucleus material.

With continued agitation, the so-formed liquid-Walled embryonic capsulesare treated by the addition to the agitated system of 0.2 gram oftetrabutyl titanate, drop by drop, which results in the cross-linking ofthe polymeric material content of the deposited liquid Wall material, toa dense self-supporting condition, within a matter of a few minutes. Ifthe drop size of the core material is of an average diameter of 100microns, the capsules will have walls of 1 to 5 microns in thickness,such thickness being governed largely by the ratio of wall material tonucleus material that is used in a given vehicle system.

Other core materials, of a watery or aqueous nature, that can beencapsulated in place of the solution of sodium ferrocyanide in waterare similar solutions of solids in either water, or ethylene glycol, andglycerine or their solutions with water or other materials, or solidswhich are not soluble in the liquid system, and all of the variousmaterials heretobefore mentioned as core materials.

EXAMPLE 21 This example is the same as Example except that the polymericmaterial intended for the capsule Walls is a copolymer of vinyl chlorideand acrylonitrile with acrylic acid groups, and having the empiricalformula:

acrylic acid polyvinyl O chloride acrylonitrile H H H G N 11 l I I I OH-cl:- -oo- Lo- 3- H ll x85% I'i El: y15z% I l H x15% Typical solvents tobe used with the above wall-forming material are cyclohexane ormethylisobutyl ketone, in the same amounts and in place of ethylenedichloride. The materials are used in the same ratio as in Example 20.

EXAMPLE 22 Example 21 is followed, except that the wall-formingpolymeric material is a copolymer of vinylidene chloride .18 andacrylonitrile with acrylic acid groups having the empirical formula:

used in the same amount.

EXAMPLE 23 Example 21 is followed, except that the wall-formingpolymeric material is of the empirical formula:

polyvinyl polyvinyl polyvinyl acetel alcohol acetate H H H H H H C H t4H;- CH, C o ll (5H y5% I; A

and used in the same amount.

Examples 20, 21, 22, and 23, exhibit the use of polymeric wall-formingmaterial that have special water-wetting groups thereon to facilitatethe encapsulation of watery nuclei, but such property does not excludethem from use in the encapsulation of non-watery materials according tothe broad aspects of the invention. However, the use of these specialmaterials is claimed in the Powell et al. application Ser. No. 192,070,filed May 3, 1962, and now abandoned.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compositions shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

What is claimed is:

1. The process of forming minute capsules en masse which comprises (a)establishing an agitated system consisting of a liquid vehicleconstituting a major portion of said system by volume and forming acontinuous liquid first phase, a second phase dispersed in said liquidvehicle consisting of minute, mobile entities of core material, and athird phase dispersed in said liquid vehicle consisting of minute,mobile, non-aqueous, liquid entities of a wall-forming solution of apolymeric material having a viscosity such that said solu tion ofwall-forming polymeric material maintains itself about the core materialin the agitated system, the said core material being wettable by saidwallforming solution and the said three phases being mutuallyincompatible, whereby said wall-forming solution deposits on and aroundsaid core entities to form a continuous liquid protective wall, and

(b) subsequently hardening the walls so formed.

2. The process of claim 1 in which the first phase is a non-aqueousorganic liquid.

3. The process of claim 1 in which the core material is a liquid.

4. The process of claim 1 in which the core material is a solid.

5. The process of claim 1 in which the core material is partly liquidand partly solid.

6. The process of claim 1 in which the core material is Water-soluble.

7. The process of forming minute capsules en masse in accordance withclaim 1 and further wherein there is curing of the depositedwall-forming solution of polymeric material by reaction with across-linking agent for it.

8. The process of forming minute capsules en masse in accordance withthe process of claim 1 and further comprising the hardening of the wallsso formed by displacing the solvent of said wall-forming solution, afterdeposit, with a solvent of greater volatility and thereafter removing asubstantial part of said displacing solvent by evaporation.

9. The process of forming minute capsules en masse in accordance withthe process of claim 1 and further comprising the step of isolating thehardened capsules from other liquids encountered during theirmanufacture.

10. The process of forming minute capsules en masse, comprising (a)establishing an agitated system consisting of a liquid vehiclecomprising a non-aqueous solvent for a wall-forming polymer and a liquidmiscible with said non-aqueous solvent and non-miscible with otherphases of the system, constituting a major portion by volume of thesystem and forming a continuous liquid first phase, a second phasedispersed in said liquid vehicle consisting of minute, mobile entitiesof core material, and a third phase dispersed in said liquid vehicleconsisting of minute, mobile, non-aqueous liquid entities of awall-forming solution of a polymeric material, the said core materialbeing wettable by said wall-forming solution and the three phases beingmutually incompatible, whereby said wall-forming solution deposits onand around said core entities to form a protective wall, and

(b) subsequently hardening the Walls so formed.

11. The process of claim in which the first phase is a non-aqueousorganic liquid.

12. The process of claim 10 in which the core material is a liquid.

13. The process of claim 10 in which the core material is a solid.

14. The process of claim 10 in which the core material is partly liquidand partly solid.

15. The process of claim 10 in which the core material is water-soluble.

16. The process of forming minute capsules en masse in accordance withthe process of claim 10 and further comprising the step of isolating thehardened capsules from other liquids encountered during theirmanufacture.

17. The encapsulation process which comprises preparing a solution of asynthetic linear polymer in an organic solvent therefor, mixing in thesolution hydrophilic solid core materials to form a dispersioncontaining uniformly dispersed core material, forming a polymer-richliquid phase coating about said uniformly dispersed core materials bymixing into the dispersion a liquid which is miscible with the organicsolvent and a non-solvent for said polymer, and said added liquid beinginert with respect to the core material and polymer; setting the coatingand separating the coated core materials.

18. The process of claim 17 wherein solid core materials, pre-coatedwith a hydrophilic coat, are used.

19. The encapsulation process which comprises: preparing a solution of apolymer in a liquid non-aqueous solvent therefor; mixing in the solutionhydrophilic solid core material to form a dispersion containinguniformly dispersed core material; forming a liquid polymer-rich phasecoating about said uniformly dispersed core material by mixing uniformlyinto the dispersion a liquid nonaqueous nonsolvent for said polymer andsaid particles and miscible with said solvent; and separating the coatedparticles.

20. The encapsulation process which comprises: preparing a solution of apolymer in a liquid non-aqueous solvent therefor; mixing in the solutionhydrophilic liquid core material to form a dispersion containinguniformly dispersed particles; forming a liquid polymer-rich phasecoating about said uniformly dispersed particles by mixing uniformlyinto the dispersion a liquid non-aqueous nonsolvent for said polymer andsaid core material and 20 miscible with said solvent; and separating thecoated core material.

21. The encapsulation process which comprises: dispersing hydrophilicliquid core material in a non-aqueous liquid, adding a polymer to saidnon-aqueous liquid to form a solution of said polymer in the non-aqueousliquid, separating a polymer-rich liquid phase to coat said corematerial by adding a liquid which is soluble in the nonaqueous liquidand a non-solvent for said polymer and said core material; andseparating the coated core material.

22. The encapsulation process. which comprises: dispersing hydrophilicsolid core material in a non-aqueous liquid, adding a polymer to thenon-aqueous liquid to form a solution of said polymer in the non-aqueousliquid, separating a polymer-rich liquid phase to coat said corematerial by adding a liquid which is soluble in the non-aqueous liquidand a non-solvent for said polymer and said core material; andseparating the coated core material.

23. The encapsulation process which comprises: preparing a solution of asynthetic linear polymer in an organic solvent therefor, adding to thesolution hydrophilic liquid core material to form a dispersion, withagitation, containing uniformly dispersed core material, forming apolymer-rich liquid phase coating about said core materials by addinginto said dispersion a liquid which is miscible with the organic solventand is a non-solvent for said polymer, said liquid being inert withrespect to the core material and polymer; hardening the coating andseparating the coated core material.

24. The process of making microcapsules comprising the steps of: forminga dispersion of colloidal droplets of an aqueous solution in acontinuous phase of a non-aqueous organic liquid substantiallyimmiscible with said aqueous solution, said non-aqueous organic liquidhaving dissolved therein an encapsulating polymeric material, and addinga non-polar organic non-solvent liquid for said encapsulating polymericmaterial to said continuous phase at a rate such that the polymericmaterial is caused to precipitate around said colloidal droplets andthereby form microcapsules, said non-polar organic non-solvent liquidbeing substantially miscible with said continuous phase andsubstantially immiscible with said colloidal droplets.

References Cited UNITED STATES PATENTS 2,399,987 5/1946 Cordie et a1.117-100 2,615,800 10/1952 Goodale 71-59 X 2,800,458 7/1957 Green 252-3162,897,121 7/1959 Wagner 167-82 2,969,331 1/1961 Brynko et al 252-3162,971,916 2/1961 Schleicher et al. 252-62.5 3,016,308 1/1962 Macaulay117-36.7 3,155,590 11/1964 Miller et al. 252-316 X 3,069,370 12/1962Jensen et al. 167-83 X FOREIGN PATENTS 795,977 6/1958 Great Britain167-83 898,668 6/1962 Great Britain 252-316 907,284 10/1962 GreatBritain 252-316 931,148 7/ 1963 Great Britain 252-316 OTHER REFERENCESDobry et al.: Phase Separation in Polymer Solution, Journal of PolymerScience, vol. 2, No. 1 (1947), pp. -100.

RICHARD D. LOVERING, Primary Examiner US. Cl. X.R.

8-79; 71-64 F, 117, DIG 1; 106-308 C, 308 M; 117-62.2, A, 100 B, 100 M;252-10, 264-4; 424-33, 35, 94, 230, 260

